Erythromycin A is a macrolide antibiotic, whose structure is characterized by a 14-member macrolactone ring with C-9 keto group. It was found by McGuire in 1952 (Antibiot. Chemother., 1952; 2:281) and for already 40 years it has been considered to be a sure and effective antimicrobial agent in the therapy of Gram-positive and some Gram-negative infections. However, in an acidic medium it is easily converted into anhydroerythromycin A, an inactive C-6/C-12 metabolite of a spiroketal structure (Kurath P. et al., Experientia 1971; 27:362). It is well known that the spirocyclization of the aglycone ring of erythromycin A is successfully inhibited by a chemical transformation of C-9 ketone or hydroxy groups in C-6 and/or C-12 position. By oximation of C-9 ketone (Djokic S. et al., Tetrahedron Lett., 1967; 1945) and by subsequent modification of the obtained 9(E)-oxime to 9-[O-(2-methoxyethoxy)-methyl-oxime-erythromycin methyl-oxime-erythromycin A (ROKSITROMICIN) (Ambrieres, G. S., FR 2,473,525 (1981)) or to 9(S)-erythromycylamin (Egan R. S. et al., J. Org. Chem., 1974; 39:2492) or its more complex oxazine derivative 9-deoxo-11-deoxy-9,11{imino[2-(2-methoxyethoxy)ethylidene]oxy}-9(S)-erythr omycin A (DIRITROMICIN) (Lugar P. et al., J. Chryst. Mol. Struct., 1979; 9:329), there are synthetized novel semisynthetic macrolides, whose basic characteristics are, in addition to enhanced stability in an acidic medium, better pharmacokinetics and a long biological half-time with regard to the parent antibiotic erythromycin A. In a third way for modifying C-9 ketone, there are used Beckmann rearrangement of 9(E)-oxime and the reduction of the obtained imino ether (Kobrehel G. et al., U.S. Pat. No. 4,328,334, 5/1982) to 11-aza-10-deoxo-10-dihydroerythromycin A (9-deoxo-9a-aza-9a-homoerythromycin A) under broadening the 14-member ketolacton ring to 15-member azalactone ring. Reductive N-methylation of 9a-NH group according to Eschweiler-Clark process (Kobrehel G. et al., BE patent 892,357, 7/1982) or preliminary protection of an amino group under conversion to corresponding N-oxides and subsequent alkylation and reduction (Bright G. M., U.S. Pat. No. 4,474,768 10/1984) yield N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A (9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A) (AZITROMICIN), a prototype of azalide antibiotics which are characterized, in addition to a broad antimicrobial spectrum including Gram-negative bacteria and intracellular microorganisms, by a specific transport mechanism to the application site, a long biological half-time and a short therapy period. EP A 0 316 128 (Bright G. M.) discloses novel 9a-allyl and 9a-propargyl derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A and U.S. Pat. No. 4,492,688 (1/1985) to Bright G. M. discloses the synthesis and antibacterial activity of the corresponding cyclic ethers.
It is further well-known that intramolecular cyclization of the aglycone ring of erythromycin A is successfully inhibited by O-alkylation of C-6 hydroxy group. 6-O-methylerythromycin A (KLARITROMICIN) achieves, at a broad antimicrobial spectrum and stability in an acidic medium, high concentrations in serum and tissues (Watanabe Y. et at., U.S. Pat. No. 4,331,803, 5/1982).
EP A 0 467 331 (1/92; Kobrehel G. et al.) discloses the synthesis and activity spectrum of O-methyl derivatives of azithromycin.